Purpose: Overexpression of the multidrug transporter, P-glycoprotein (P-gp) may contribute to tumor cell drug resistance to P-gp substrates such as doxorubicin (D) and paclitaxel (T). Co-administration of these drugs with a P-gp inhibitor such as PSC-833 offers the potential of overcoming this mechanism of drug resistance. The purpose of this Phase I trial was to establish (1) the MTD of doxorubicin by IV bolus followed by paclitaxel by a 1 hr infusion (DT); (2) the MTD of DT combined with PSC (DTP), without and with G-CSF; and (3) the pharmacokinetic interactions of PSC with D and T. Methods: Patients received DT followed 3 weeks later by reduced doses of DT with PSC. 33 patients (pts) with a wide variety of refractory (mean 2 prior chemotherapy regimens) malignancies were enrolled. 7 pts received D 40 mg/m2 and T 175 mg/m2. Six of 7 had grade 4 neutropenia, and 0/7 fever. The next dose level was D 35 mg /m2 and T 150 mg/m2 (n=10) and this was defined as the MTD as 5 of 10 had grade 4 neutropenia with 2 of 10 experiencing fever also. After one cycle of DT alone, pts received reduced doses of DT with PSC at 5 mg/kg qid p.o. x 12 doses. D and T were administered after the 5th dose of PSC in 3 cohorts . For determination of MTD, 21 pts were treated with the combination. Results: The MTD of the combination was 15 mg/m2 of D and 80 mg/m2 of T with 7 of 8 pts experiencing grade 4 neutropenia and only 2 with fever also. The dose limiting toxicity for both DT and DTP was neutropenia without thrombocytopenia. We then proceeded to establish the MTD of DTP with G-CSF. With G-CSF, DTP was well tolerated by 6 pts at 20 mg/m2 D and 80 mg/m2 T. The next cohort (n=6) was treated at 20 mg/m2 D and 90 mg/m2 T and defined the MTD as 2/6 patients grade 4 neutropenia with fever and 3/6 grade 3 thrombocytopenia. Significant non-hematologic toxicities included one grade 3 supraventricular tachyarrythmia, eight grade 3 constipations, and two grade 3 hypertension but no CHF, bradyarrythmias or typhilitis. Other non-hematologic toxicities were transient elevation of bilirubin and transaminases with PSC. In 9 pts PSC produced significant but rapidly reversible ataxia requiring dose reduction to 4 mg/kg in 8 patients. All 33 pts are evaluable for response. 5 partial remissions were observed (2 non-small cell lung, 12 +mos and 4+ mos; ovarian, 5+ mos, unknown primary 4+ mos and fallopian tube, 11 mos.) and 2 minor responses (ovarian, 6 mos.; mediastinal germ cell, 4 mo). Paired pharmacokinetics with and without PSC revealed substantial drug interactions with both D and T. The plasmsa terminal half-life of D was prolonged by 77% and of T by 96%, when co-administered with PSC (p< 0.001 for both compared for both D and T without PSC). The mean plasma residence times of D and T were increased by 84% and 165% respectively (p<0.001) for both. Conclusion: PSC 833 can be administered safely with doxorubicin and paclitaxel. The pharmacokinetic interactions provide a further rationale for dose modifications of D and T when combined with PSC. Further Phase II/III trials are required to assess the role of this combination for the treatment of refractory solid tumors.